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Vol. 58, No. 2
(4H, m). ESI-MS (positive) m/z: 218.0802 [MꢄH]ꢄ.
558.1746).
5o: 1H-NMR (DMSO-d6) d: 1.82 (d, 3H, Jꢂ6.9 Hz), 3.80 (3H, s), 3.81
(3H, s), 5.61 (1H, q, Jꢂ6.9 Hz), 6.92—6.98 (4H, m), 7.60 (2H, d, Jꢂ9.0
Hz), 7.7 (2H, d, Jꢂ9.0 Hz), 7.84 (4H, m), 8.16 (1H, s), 9.76 (1H, s), 10.81
(1H, s), 11.20 (1H, s), 11.57 (1H, s). HR-ESI-MS (positive) m/z: 4590.1621
[MꢄH]ꢄ (Calcd for C28H28N7O2S2: 590.1644).
1-Bromo-3-phthalimido-2-butanone (3) To a stirred solution of 2
(2.17 g, 10 mmol) in AcOH (20 ml), bromine water (1.76 g, 11 mmol) was
added drop-wise. After complete addition, stirring was continued at room
temperature for 1 h. The reaction mixture was then poured onto ice cold
water, and the solid product was filtered, washed with H2O, dried, and crys-
tallized from 95% ethanol. 1H-NMR (CDCl3) d: 1.67 (3H, d, Jꢂ5.4 Hz),
3.99 (2H, dd, Jꢂ11.4 Hz), 5.22 (1H, q, Jꢂ5.4 Hz), 7.73—7.88 (4H, m). ESI-
MS (positive) m/z: 295.9926 [MꢄH]ꢄ.
General Procedure for the Preparation of 2-N-Phthalimide Acetic
Acid (7a) and 4-N-Phthalimide Butyric Acid (7b) Phthalandione (2.96
g, 20 mmol) and the appropriate amino acid (1.2 eq) were suspended in
AcOH (20 ml). The suspension was refluxed for 2 h and then cooled and
poured into water (20 ml). The resulting precipitate was filtered, washed with
water, and dried to give the desired product.
General Procedure for the Preparation of 3-Phthalimido-2-oxo-n-
butyraldehyde-bis-(4-alkyl or aryl)thiosemicarbazone (5a—o) A solu-
tion of 3 (296 mg, 1 mmol) in DMSO/H2O (4 : 1, 2 ml) was heated at 80 °C
for 3 h. The appropriate thiosemicarbazide (2 mmol) in hot 95% ethanol
was added and stirring under reflux was continued for 1—3 h, during which
period a precipitate was formed. The precipitate was filtered, washed with
ethanol, dried, and purified by flash chromatography on silica gel to afford
5a—o.
7a: 1H-NMR (CDCl3) d: 4.50 (2H, s), 7.74—7.76 (2H, m), 7.89—7.91
(2H, m). ESI-MS (positive) m/z: 206.0511 [MꢄH]ꢄ.
7b: 1H-NMR (DMSO-d6) d: 1.79—1.85 (2H, m), 2.56 (2H, t), 3.59 (2H, t),
7.80—7.87 (4H, m), 12.05 (1H, s). ESI-MS (positive) m/z: 297.9875 [Mꢄ
H]ꢄ.
5a: 1H-NMR (CDCl3) d: 1.67 (3H, d, Jꢂ7.2 Hz), 3.44—3.48 (12H, m),
5.21 (1H, q, Jꢂ7.2 Hz), 7.72 (1H, s), 7.72—7.84 (4H, m), 9.36 (1H, s),
12.23 (1H, s). HR-ESI-MS (positive) m/z: 434.1389 [MꢄH]ꢄ (Calcd for
C18H24N7O2S2: 434.1433).
General Procedure for the Preparationof 1-Bromo-3-phthalimido-2-
aceton (8a) and 1-Bromo-3-phthalimido-2-pentanone (8b) A solution
of 7a or 7b (10 mmol) in SOCl2 (5 ml) was refluxed for 2 h. After that, all
volatiles were removed under reduced pressure and the crude acid chloride
thus obtained was dissolved in toluene (1 ml) and added dropwise to an ice-
cold solution of new CH2N2 [prepared from nitrosomethyl urea (6 g) and
KOH (5 g) in water (20 ml) in ether (45 ml)] over 20 min. The mixture was
allowed to reach room temperature and excess diazomethane was destroyed
with a few drops of AcOH. After addition of satd NaHCO3 solution (10 ml),
the ether layer was separated and the aqueous portion extracted with ether
(2ꢆ20 ml). The combined ether fractions were dried, evaporated under re-
duced pressure. Hydrobromic acid (47%, 1 ml) was added dropwise to a so-
lution of N-Pht a-diazoketones in THF (10 ml) at 0 °C. After stirring at
room temperature for 1 h, the reaction was neutralized with satd NaHCO3
solution and extracted with ethyl acetate (3ꢆ30 ml). The combined ethyl ac-
etate layer was washed with brine, dried and evaporated under reduced pres-
sure to give the corresponding 8a or 8b which were purified by recrystalliza-
tion.
5b: 1H-NMR (DMSO-d6) d: 1.14—1.64 (12H, m), 1.62 (3H, d, Jꢂ6.9
Hz), 4.39—4.41 (2H, m), 5.46 (1H, q), 7.58 (1H, d, Jꢂ8.1 Hz), 7.68 (1H, d),
7.82 (1H, s), 7.86—7.88 (4H, m), 11.56 (2H, s). HR-ESI-MS (positive) m/z:
484.1545 [MꢄNa]ꢄ (Calcd for C20H27N7O2NaS2: 484.1565).
5c: 1H-NMR (DMSO-d6) d: 0.74—1.98 (23H, m), 4.10 (2H, m), 5.46
(1H, q), 7.58 (1H, d), 7.70 (1H, d), 7.82 (4H, m), 7.89 (1H, s), 11.54 (1H, s),
11.56 (1H, s). HR-ESI-MS (positive) m/z: 542.2388 [MꢄH]ꢄ (Calcd for
C26H36N7O2S2: 542.2372).
1
5d: H-NMR (CDCl3) d: 1.73 (3H, d), 4.37 (m, 4H), 5.34 (m, 5H), 5.92
(m, 1H), 7.39 (s, 1H), 7.79 (m, 4H), 9.75 (s, 1H), 11.71 (s, 1H). HR-ESI-MS
(positive) m/z: 458.1406 [MꢄH]ꢄ (Calcd for C20H24N7O2S2: 458.1433).
5e: 1H1NMR (DMSO-d6) d: 1.62 (3H , d, Jꢂ6.9 Hz), 4.73—4.88 (4H, m),
5.49 (1H, q, Jꢂ6.9 Hz), 7.22—7.34 (10H, m), 7.68—7.81 (4H, m), 7.94
(1H, s), 8.50 (1H, t, Jꢂ6.3 Hz), 8.57 (1H, s, Jꢂ6.3 Hz), 11.66 (1H, s), 11.71
(1H, s, NH). HR-ESI-MS (positive) m/z: 558.1744 [MꢄH]ꢄ (Calcd for
C28H281N7O2S2: 558.1746).
1
8a: H-NMR (CDCl3) d: 4.01 (2H, s), 4.78 (2H, s), 7.75—7.77 (2H, m),
7.88—7.90 (2H, m). ESI-MS (positive) m/z: 281.9760 [MꢄH]ꢄ.
1
8b: H-NMR (CDCl3) d: 2.00—2.04 (2H, m), 2.72 (2H, t), 3.73 (2H, t),
5f: H-NMR (DMSO-d6) d: 1.62 (3H, d, Jꢂ6.9 Hz), 4.69—4.86 (4H, m),
5.48 (1H, q, Jꢂ6.9 Hz), 7.29—7.39 (8H, m), 7.68—7.80 (4H, m), 7.92 (1H,
s), 8.52 (1H, t, Jꢂ6.3 Hz), 8.63 (1H, s, Jꢂ6.3 Hz), 11.65 (1H, s), 11.74
(1H, s). HR-ESI-MS (negative) m/z: 624.0812 [MꢅH]ꢅ (Calcd for
C28H24N7O2Cl2S2: 624.0805).
3.92 (2H, s), 7.71—7.74 (2H, m), 7.83—7.86 (2H, m). ESI-MS (positive)
m/z: 310.0077 [MꢄH]ꢄ.
General Procedure for the Preparation of Compounds 9a—d Com-
pounds 9a—d were prepared from 8a or 8b using the general procedure for
the preparation of Compounds 5a—o.
1
5g: H-NMR (DMSO-d6) d: 1.73 (3H, d, Jꢂ6.9 Hz), 5.68 (1H, q, Jꢂ6.9
9a: 1H-NMR (DMSO-d6) d: 4.91 (2H, s), 7.20—7.28 (2H, m), 7.36—7.46
(4H, m), 7.47—7.63 (4H, m), 7.78—8.16 (5H, m), 9.77 (1H, s), 10.47 (1H,
s), 11.31 (1H, s), 12.23 (1H, s). HR-ESI-MS (negative) m/z: 514.1118
[MꢅH]ꢅ (Calcd for C25H20N7O2S2: 514.1120).
Hz), 7.21—7.43 (6H, m), 7.60—7.71 (4H, m), 7.84 (4H, m), 8.04 (1H, s),
9.78 (1H, s), 9.80 (1H, s), 11.96 (1H, s), 11.98 (1H, s). HR-ESI-MS (nega-
tive) m/z: 528.1238 [MꢅH]ꢅ (Calcd for C26H22N7O2S2: 528.1271).
1
5h: H-NMR (DMSO-d6) d: 1.70 (3H, d, Jꢂ7.2 Hz), 5.64 (1H, q, Jꢂ7.2
9b: 1H-NMR (DMSO-d6) d: 4.91 (2H, s), 7.42—7.62 (8H, m), 7.81—
7.90 (5H, m), 9.82 (1H, s), 10.53 (1H, s), 11.38 (1H, s), 12.32 (1H, s). HR-
ESI-MS (negative) m/z: 582.0321 [MꢅH]ꢅ (Calcd for C25H19Cl2N7O2S2:
582.0340).
Hz), 7.20—7.46 (8H, m), 7.48—7.88 (4H, m), 8.06 (1H, s), 9.41 (1H, s),
9.65 (1H, s), 12.03 (1H, s), 12.14 (1H, s). HR-ESI-MS (negative) m/z:
564.1132 [MꢅH]ꢅ (Calcd for C26H20N7O2F2S2: 564.1083).
5i: 1H-NMR (DMSO-d6) d: 1.71 (3H, d, Jꢂ7.2 Hz), 5.66 (1H, q, Jꢂ
7.2 Hz), 7.56—7.71 (8H, m), 7.84 (4H, m), 8.03 (1H, s), 9.84 (2H, s), 12.04
(1H, s), 12.05 (1H, s). HR-ESI-MS (negative) m/z: 683.9463 [MꢅH]ꢅ
(Calcd for C26H20N7O2Br2S2: 683.9481).
1
9c: H-NMR (DMSO-d6) d: 1.78—1.82 (2H, m), 3.00 (2H, t), 3.72 (2H, t),
7.18—7.23 (2H, m), 7.34—7.38 (4H, m), 7.50—7.56 (4H, m), 7.56—7.81
(4H, m), 7.80 (1H, s), 9.83 (1H, s), 10.26 (1H, s), 11.27 (1H, s), 12.10 (1H,
s). HR-ESI-MS (negative) m/z: 542.1434 [MꢅH]ꢅ (Calcd for
C27H25N7O2S2: 542.1433).
1
5j: H-NMR (DMSO-d6) d: 1.71 (3H, d, Jꢂ6.9 Hz), 5.65 (1H, q, Jꢂ6.9
Hz), 7.21—7.58 (8H, m), 7.84 (4H, m), 8.03 (1H, s), 9.77 (1H, s), 9.81 (1H,
s), 11.99 (2H, s). HR-ESI-MS (negative) m/z: 564.1083 [MꢅH]ꢅ (Calcd for
C26H20N7O2F2S2: 564.1131).
9d: 1H-NMR (DMSO-d6) d: 1.77—1.81 (2H, m), 3.00 (2H, t), 3.71 (2H, t),
7.39—7.42 (4H, dd), 7.52—7.60 (4H, dd), 7.61—7.91 (4H, m), 7.80 (1H, s),
9.87 (1H, s), 10.31 (1H, s), 11.35 (1H, s), 12.19 (1H, s). HR-ESI-MS (nega-
tive) m/z: 610.0643 [MꢅH]ꢅ (Calcd for C27H23Cl2N7O2S2: 610.0653).
1
5k: H-NMR (DMSO-d6) d: 1.72 (d, 3H), 5.66 (dd, 1H), 7.45—7.74 (m,
8H), 7.76 (m, 4H), 8.03 (s, 1H), 9.85 (d, 2H), 12.03 (d, 2H). HR-ESI-MS
(negative) m/z: 596.0497 [MꢅH]ꢅ (Calcd for C26H20N7O2Cl2S2: 596.0497).
5l: 1H-NMR (DMSO-d6) d: 1.71(3H, d, Jꢂ6.8 Hz), 5.66 (1H, q, Jꢂ6.8
Hz), 7.79—7.81 (6H, m), 7.83 (4H, m), 8.04 (1H, s), 9.94 (1H, s), 9.99 (1H,
s), 12.15 (2H, s). HR-ESI-MS (negative) m/z: 663.9700 [MꢅH]ꢅ (Calcd for
C26H18N7O2Cl4S2: 663.9712).
Acknowledgement Financial support of Beijing Municipal Commission
of Commerce is acknowledged. Technical assistance of professor Wan Lin is
greatly appreciated.
1
References
5m: H-NMR (DMSO-d6) d: 1.73 (3H, d, Jꢂ7.2 Hz), 5.66 (1H, q, Jꢂ7.2
1) Gudmundsson K. S., Johns B. A., Allen S. H., Bioorg. Med. Chem.
Lett., 18, 1157—1161 (2008).
2) Gudmundsson K. S., Johns B. A., Bioorg. Med. Chem. Lett., 17,
2735—2739 (2007).
3) Tomé J. P. C., Neves M. G. P. M. S., Tomé A. C., Cavaleiro J. A. S.,
Mendonça A. F., Pegado I. N., Duarteb R., Valdeirab M., Bioorg. Med.
Chem., 13, 3878—3888 (2005).
Hz), 7.77—7.87 (4H, m), 8.03—8.47 (6H, m), 8.61 (1H, s), 9.75 (1H, s),
10.05 (1H, s), 10.34 (1H, s), 12.32 (1H, s). HR-ESI-MS (negative) m/z:
800.0756 [MꢅH]ꢅ (Calcd for C30H18N7O2F12S2: 800.0753).
5n: 1H-NMR (DMSO-d6) d: 1.65 (3H, d, Jꢂ6.9 Hz), 2.24 (3H, s), 2.33
(3H, s), 5.63 (1H, q, Jꢂ6.9 Hz), 7.10 (2H, d, Jꢂ8.7 Hz), 7.22 (2H, d, Jꢂ8.4
Hz), 7.32 (2H, d, Jꢂ8.4 Hz), 7.55 (2H, d, Jꢂ8.4 Hz), 7.35—7.82 (4H, m),
8.33 (1H, s), 9.45 (1H, s), 9.66 (1H, s), 11.94 (1H, s), 12.14 (1H, s). HR-
ESI-MS (positive) m/z: 558.1744 [MꢄH]ꢄ (Calcd for C28H28N7O2S2:
4) Yin M. B., Cheng M., Ye Q. R., Yang H., M., Gao Y. J., Wang L., Liu